Myasthenia gravis (MG) is the most common disorder of the neuromuscular junction (NMJ), affecting 400-600 per million people in various populations. It is caused by autoantibodies against muscle nicotinic acetylcholine receptor (AChR) and MuSK, a receptor tyrosine kinase that is critical for Agrin-induced AChR concentration at the NMJ. However, some MG patients do not carry AChR or MuSK antibodies (Abs) (hereafter referred to as double seronegative MG, DNMG). The pathological mechanisms of DNMG are not well understood, leaving a void that hinders diagnosis and efficient treatment of inflicted patients. Recent studies including ours demonstrate that Agrin and LRP4 Abs are present in DNMG patients, identifying potential pathological mechanisms. However, the clinical significance of these findings is unknown. The prevalence of the Abs in DNMG is either unknown or extremely variable in the literature. Due to limited number of DNMG patients and inconsistent inclusion criteria and limited patient follow-up in previous studies, little is known about epidemiology and clinical features of Agrin or LRP4 Ab+ MG. Whether and how these Abs are pathogenic remain poorly understood. In this study, we will collaborate with 27 MG Centers in the United States that routinely see > 4,500 MG patients including 789 DNMG. We will determine the prevalence of Agrin and LRP4 Abs in this large cohort of DNMG patients and characterize the epidemiology, clinical feature and responses to treatments of DNMG patients with Agrin and LRP4 Abs. We will determine whether Agrin and LRP4 Abs are pathogenic and investigate molecular and cellular pathological mechanisms of Agrin and LRP4 Abs. This multicenter proposal will allow us to identify two new causes for MG. It will provide valuable information regarding the prevalence of Agrin and LRP4 Abs in DNMG patients, the epidemiology of these new forms of MG and association with clinical features, severity, diagnostic tests and responses to treatments, and pathological mechanisms. It will contribute to the development of novel therapeutic strategies against this devastating disease.